Genes asociados a displasias esqueléticas. Diagnóstico e implicación en el asesoramiento genético (1998-2012)

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología. Fecha de lectura: 22-01-2016Esta tesis tiene embargado el acceso al texto completo hasta el 22-07-2017Instituto de Investigación Sanitaria. Fundación Jiménez DíazLas displasias esqueléticas son un amplio campo de estudio que requiere unidades disciplinares de las distintas especialidades involucradas en su desarrollo. Esta tesis, basada en un trabajo principalmente asistencial, ha intentado dar respuesta al mayor número de demandas solicitantes de displasias esqueléticas recogidas en dos periodos: desde su inicio a 2006, y tras la concesión de un proyecto específico, de 2007 a 2012. En ese intento se han puesto a punto nuevos genes y nuevas herramientas diagnósticas que han permitido caracterizar mutaciones familiares que han facilitado la realización de un asesoramiento genético individual, familiar y reproductivo, fin último del estudio genético. Ante alteraciones ecográficas el gen FGFR3 juega un papel importante en el diagnóstico, con una sensibilidad de hasta el 60% en los fetos con hipoplasia torácica y micromelia. El estudio de las craneosinostosis aisladas sindrómicas requiere de un primer cribado del exón 7 del gen FGFR3 así como de los exones 7 y 8 del gen FGFR2, seguido de la aplicación de la secuenciación masiva en una segunda aproximación diagnóstica. El estudio de la talla baja disarmónica requiere de la secuenciación seriada del gen FGFR3, gen SHOX y gen COMP. Existen otras tallas bajas disarmónicas con fenotipos característicos reconocibles que dirigen el estudio molecular de forma concreta (genes RMRP y COMP). La puesta a punto del gen SLC26A2 se realizó ante un resultado molecular no concluyente en una pareja y su hija afecta. El estudio de la talla baja idiopática se centra en las alteraciones en el gen SHOX. La selección de los pacientes y la aplicación de una escala clínica que cribe los pacientes a estudio es necesaria para optimizar recursos y expectativas diagnósticas. Una buena exploración y recogida de datos, así como dar una explicación detallada de las alteraciones encontradas, es un requisito imprescindible para orientar el estudio molecular y, ante un primer resultado negativo, tener la información para poder proponer otros diagnósticos diferenciales. Esta premisa es independiente de la técnica molecular que se utilice: desde la robusta y conocida secuenciación de sanger hasta las nuevas herramientas diagnósticas de secuenciación masiva

ADHD Symptomatology, Executive Function and Cognitive Performance Differences between Family Foster Care and Control Group in ADHD-Diagnosed Children

Children in foster care have a high prevalence of attention deficit and hyperactivity disorder (ADHD) diagnosis, together with other difficulties in inattentive/hyperactive behaviors, executive and cognitive processes. Early exposure to adversity is a risk factor for developing ADHD via neurodevelopmental pathways. The goal of this research is (a) to study the cognitive and executive performance and inattentive/hyperactive behavior of ADHD-diagnosed children living in foster families in Spain, and (b) to analyze the role of placement variables in their performance. The sample was composed of 102 ADHD-diagnosed children aged 6- to 12-years-old, divided into two groups: 59 children living with non-relative foster families and 43 children not involved with protection services. Children’s executive function–inhibition, working memory, flexibility, attention, intellectual capacity, verbal comprehension, perceptive reasoning, working memory and processing speed were assessed using objective testing measures. At the same time, parents and teachers reported on children’s inattentive, hyperactive and impulsive behaviors. Children in foster care obtained lower scores in the general ability index than the control group after controlling the age at assessment. However, no differences were found in executive processes. Regarding placement factors, children with shorter exposure to adversities in their birth families and more time in foster care showed better executive performance. Professionals should consider the placement history of children in foster care and its influence on their symptomatology and cognitive capacities

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies

Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue – GLA p.(Arg118Cys) –, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands’ close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease, since the allelic frequency in stroke patients was 0.0087 (p=0.0185 vs the general population). The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for “rare” conditio

Concordancia en el curso del trastorno bipolar en gemelas monocigóticas

Appeal from convictions for possession of methamphetamine, enhanced to a second degree felony, and possession of marijuana, a Class A misdemeanor, in the Third Judicial District, Salt Lake County, the Honorable Denise P. Lindberg presidin

Duplications in Symptomatic Females

Xq28 microduplications including the MECP2 gene constitute a 100% penetrant X-linked syndrome in males caused by overexpression of normal MeCP2 protein. A small number of cases of affected females have been reported. This can be due to the location of the duplicated material into an autosome, but it can also be due to the location of the duplicated material into one of the X chromosomes and random or unfavorable skewed X chromosome inactivation, which is much more likely to occur but may be underdiagnosed because of the resulting broad phenotypic spectrum. In order to contribute to the phenotypic delineation of Xq28 microduplications including MECP2 in symptomatic females, the authors present clinical and molecular data on 3 patients illustrating the broad phenotypic spectrum. Our finding underlines the importance of quantitative analysis of MECP2 in females with intellectual disability and raises the question of the indication in females with borderline intellectual performances or learning difficulties

Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease

We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140 carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in C haplotypes (40.1%), while A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles ≥50 CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively, of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much more diverse, in alleles of ≥27 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms. Spanish HD haplotypes are characterised by a high genetic diversity, potentially admixed with other non-Caucasian populations, with a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion

Cross-national study of quantity comparison abilities and math performance using Numeracy Screener

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